FIG 9.

Schematic illustration of the redox regulation and metabolic dependency of Zika virus replication. (A) ZIKV induces a transient stabilization and activation of the antioxidant transcription factor Nrf2. Pharmacological inhibition of de novo GSH synthesis and knockdown of Nrf2, and the NADPH regenerating enzymes G6PD and 6PGD (not depicted), enhance viral replication and cell death, demonstrating an antiviral role (–) of Nrf2 signaling and GSH redox cycle, while ROS seem to facilitate viral replication (+). (B) Metabolomic studies and metabolic flux assays suggest that the antiviral effects of the NAD antimetabolite 6-AN likely involve multiple mechanisms, including NAD depletion and interference with NAD-dependent metabolic processes. 6-AN inhibits glycolysis and the PPP (red X), which are required for energy production and synthesis of nucleotides. Mitochondrial metabolism (blue lines) exerts a compensatory role in viral replication when glycolysis is inhibited.